J. Oleksy

Comparison of Methylated Prostaglandin E2 Analogues Given Orally in the Inhibition of Gastric Responses to Pentagastrin and Peptone Meal in Man

In 32 healthy male volunteers the effects on gastric secretion of three methyl analogues of prostaglandin (PG) E2 have been studied, namel, 15 (R) -15-methyl PGE2 methyl ester, 15 (S) -15-methyl PGE2 methyl ester, and 16, 16-dimethyl PGE2. Secretion was measured for 30 min and a PG analogue at doses ranging from 1.25 to 2.5 mug per kg or a placebo was administered. Gastric secretion was then stimulated either by an intravenous infusion of pentagastrin (2 mug per kg-hr) or by a peptone meal with acid secretion determined by intragastric titration technique. The tests were randomized and double blind. All three methyl PG analogues exhibited a profound and prolonged inhibitory action on gastric acid and pepsin secretion induced by pentagastrin. PG analogues caused almost complete inhibition of gastric acid response to a peptone meal accompanied by a significant reduction in the serum concentration of immunoassayable gastrin. Except with the highest dose of PG (S) -15-methyl PGE2 methyl ester, which caused abdominal discomfort and single episodes of diarrhea in some subjects, no symptoms or untoward biochemical effects were observed. It is concluded that these methylated PG analogues are very potent inhibitors of gastric acid and pepsin secretion stimulated by pentagastrin or a meal and may have clinical potential in the treatment of peptic ulcer.

Effect of Glucagon on Meal-Induced Gastric Secretion in Man

The effect of glucagon on gastric acid and pepsin secretion, basal or stimulated by a meal, pentagastrin and histamine, was studied in duodenal ulcer patients. Intravenous glucagon infused in graded doses ranging from 6.2 to 50 mug per kg-hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 40% of the control level at the dose of 50 mug per kg-hr. Acid inhibition was paralleled by a decrease in the pepsin output and serum calcium level and was accompanied by a rise in the blood glucose concentration. Glucagon used in a standard dose of 25 mug per kg-hr produced about 50% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in the serum gastrin level measured by radioimmunoassay. Histamine-induced secretion was only slightly inhibited by glucagon, and the degree of inhibition for acid (25%) and pepsin (20%) secretion was statistically insignificant.

Cholecystokinin in the inhibition of gastric secretion and gastric emptying in humans

Cholecystokinin (CCK) is known to inhibit gastric acid secretion and gastric emptying but its physiological role in the inhibition of gastric functions is not settled. In this study performed on 16 young male subjects, gastric acid secretion and emptying rate were determined after intragastric administration of 8% peptone meal alone or in combination with intravenous infusion of graded doses of CCK-8 (5-80 pmol/kg.h) or with addition of vegetable oil to meal without or with pretreatment with loxiglumide, a specific CCK antagonist. CCK-8 infusion at lower dose (5 pmol/kg.h) was ineffective but at higher doses (20-80 pmol/kg.h) it resulted in a significant reduction in acid output by 39 and 43% and a decrease in gastric emptying from 54% to 40 and 22%, respectively. Pretreatment with loxiglumide abolished almost completely the inhibition of both gastric acid and gastric emptying by CCK-8. Fat added to peptone meal reduced gastric acid secretion by 42-65% and decreased gastric emptying to 24-32%. The pretreatment with loxiglumide tended to reduce fat-induced inhibition of gastric acid secretion and gastric emptying but the difference in the inhibition of gastric functions between the tests without and with loxiglumide was not significant. This study provides evidence that exogenous CCK administered at pharmacological doses is a potent inhibitor of gastric acid secretion and gastric emptying and probably acts via specific CCK receptors. In contrast, fat induces inhibition of gastric acid secretion and gastric emptying that cannot be fully attributed to hormonally acting CCK.

Effect of metiamide, a histamine H2-receptor antagonist, on gastric response to histamine, pentagastrin, insulin, and peptone meal in man

The action of metiamide on histamine-, and pentagastrin-, insulin-, and meal-induced maximal gastric secretion was studied in six duodenal ulcer patients. Gastric acid secretion in tests with histamine, pentagastrin, or insulin stimulation was collected by a simple aspiration technique whereas that induced by a peptone meal was determined by the modified intragastric titration method of Fordtran and Walsh, in which acid output was measured by monitoring the rate at which 0.5 M sodium bicarbonate had to be added to keep the gastric content at the initial value of pH 5.0. Metiamide produced a dose-related inhibition of histamine-induced acid and pepsin outputs, and the dose required for 50% inhibition was about 1 mg/kg-hr. Metiamide given intravenously in a dose of 1 mg/kg-hr caused a strong and immediate inhibition of gastric acid and pepsin secretion induced by all stimuli used. Similar inhibition was observed after intragastric administration of metiamide in a single dose of 4 mg/kg. We conclude that metiamide is a very strong inhibitor of gastric acid and pepsin secretion induced by a variety of secretory stimuli and that it might deserve attention from clinicians as a side-effect-free depressant of acid secretion in the treatment of peptic ulcer disease.

Effect of Medical and Surgical Vagotomy on Gastric Response to Graded Doses of Pentagastrin and Histamine

Summary In three groups of duodenal ulcer patients—I, 22 patients pretreated with hexamethonium and atropine (medical vagotomy); II, 15 patients with surgical vagotomy; and III, 11 patients with both medical and surgical vagotomy—the acid responses to graded doses of histamine and pentagastrin infused intravenously were studied. Medical as well as surgical vagotomy lowered the dose response curve at all levels, shifting it to the right. Medical vagotomy resulted in the reduction of HCl secretion to similar degree for histamine and pentagastrin, whereas surgical vagotomy reduced more markedly the response to pentagastrin than to histamine. A strong correlation was shown between the maximal responses to pentagastrin and histamine before and after medical and surgical vagotomy. A significant correlation was demonstrated also between the prevagotomy maximal acid output to both stimulants and the percentage of reduction of HCl secretion to these stimulants induced by medical and surgical vagotomy.

Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients.

The effect of somatostatin, a growth hormone release-inhibiting hormone (GH-RIH), on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 μg/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 μg/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dosedependent reduction in serum growth hormone and insulin levels measured by radio-immunoassay. GH-RIH used in a single dose of 2.5 μg/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.

Prostaglandins and Vagal Stimulation of Gastric Secretion in Duodenal Ulcer Patients

The effects of a stable prostaglandin (PG) E2 analog (15-R-15 methyl PGE2) and aspirin, a potent inhibitor of cyclooxygenase, on modified sham-feeding (MSF)-stimulated gastric secretion and serum gastrin and pancreatic polypeptide (PP) levels were measured in patients with duodenal ulcer. PGE2 analog given orally significantly reduced gastric acid and pepsin secretion and suppressed serum PP but not gastrin responses to MSF. Suppression of PG generation in the gastric mucosa did not influence the secretory or hormonal responses to MSF. This study shows that endogenous PGs are not involved in the control of vagally stimulated gastric secretion, but exogenous PGE2 analog is an effective inhibitor of such secretion and merits clinical evaluation in the treatment of duodenal ulcer.

Effect of atropine on gastric acid response to graded doses of pentagastrin and histamine in duodenal ulcer patients before and after vagotomy

SummaryGastric acid secretion—basal and stimulated by increasing doses of Pentagastrin or histamine—has been examined before and after administration of different doses of atropine in 20 duodenal ulcer patients with intact vagi and in 12 after surgical vagotomy. Atropine greatly depressed basal acid output and lowered the dose response curves to Pentagastrin and histamine, shifting them to the right. Significant inhibition of acid output was observed in basal secretion and at lower dose levels of gastric stimulation, whereas the maximal acid output remained unchanged both in patients with intact vagi and after surgical vagotomy.Maximum inhibition of basal and stimulated acid secretion was observed at an atropine dose of 25 µg./kg./hr. Doubling this dose of atropine did not result in further reduction of gastric acid secretion.

Effect of ranitidine, a new H2-antagonist, on gastric and pancreatic secretion in duodenal ulcer patients

The effects of a new H2-receptor blocker, ranitidine, given intravenously (for comparison with cimetidine) or orally on gastric and pancreatic secretion have been studied in duodenal ulcer patients. Ranitidine appears to be several times more potent and a longer-acting inhibitor of gastric secretion than cimetidine. This H2 blocker does not affect pancreatic bicarbonate and enzyme secretion.

Effect of orally administered 15(R)-15-methyl prostaglandin E2 and/or an anticholinergic drug on meal-induced gastric acid secretion and serum gastrin level in patients with duodenal ulcers.

The purpose of the present series of tests was to measure and compare the effects of ingestion of gelatin capsules containing 15(R)-15-methyl PGE2 (PG) and/or an anticholinergic drug (methscopolamine bromide, Pamine) on meal-induced gastric acid secretion and serum gastrin level. Eleven duodenal ulcer patients were stimulated by a 5% peptone meal. Acid secretion was determined by the intragastric titration technique, and serum gastrin was measured by radioimmunoassay. The tests were randomized and double-blind. PG alone given 30 min before a test meal at a dose of 50 micrograms or 100 micrograms produced no side effects and inhibited meal-stimulated acid secretion by about 43% and 55%, respectively. Gastric acid inhibition after a single dose of PG was most pronounced in the first hour of a test meal and was accompanied by almost complete suppression of the meal-induced serum gastrin level. Pamine alone in a dose of 2.5 mg reduced gastric acid response to a meal by about 29% but caused a further rise of postprandial serum gastrin level over control values. The combination of PG, 50 micrograms, and Pamine, 2.5 mg, did not result in significantly greater acid inhibition (about 48%) than when either compound was given alone. When the higher dose of PG (100 micrograms) was given together with Pamine (2.5 mg), the degree of inhibition produced by PG alone was not changed. It is concluded that PG given orally in capsules is a potent inhibitor of gastric acid and serum gastrin response to a meal and that this effect may be of potential value in the treatment of peptic ulcer disease.